CN103547302A

CN103547302A - Dose setting mechanism and injection device

Info

Publication number: CN103547302A
Application number: CN201280024247.6A
Authority: CN
Inventors: D.A.普伦普特里
Original assignee: Sanofi Aventis Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 2011-03-25
Filing date: 2012-03-22
Publication date: 2014-01-29
Anticipated expiration: 2032-03-22
Also published as: EP2688611B1; PL2688611T3; EP2688611A1; JP6059706B2; MY160872A; CA2829840C; AR085486A1; JP2014516598A; CN103547302B; RU2601987C2; RU2013147608A; AU2012234469A1; HUE025080T2; IL228256A; WO2012130705A1; SG193285A1; US20140025016A1; NZ615855A; ES2543439T3; BR112013024658A2

Abstract

A dose setting mechanism (1) for a resettable drug delivery device is provided comprising a dose setting member (3) and a drive member (4) for driving a piston rod in a distal direction during dose dispensing, wherein the drive member (4) comprises a proximal drive member (4'') and a distal drive member (4'). Further, a first clutch is provided for releasably coupling the proximal drive member (4'') and the distal drive member (4'). A spring means (7) biases the proximal drive member (4'') and the distal drive member (4') in the coupled state during dose setting and dose dispensing. According to one aspect of the invention engaging means (3a, 4a) are provided associated to the proximal drive member (4'') and to the dose setting member (3), wherein the engaging means (3a, 4a) are designed and arranged such that the proximal drive member (4'') entrains the dose setting member (3) in the distal direction during dose setting but allows a relative axial movement of the proximal drive member (4'') with respect to the dose setting member (3) in the proximal direction. Further, the invention refers to an injection device with such a dose setting mechanism.

Description

Dosing mechanism and injection device

Technical field

The present invention relates to a kind of dosing mechanism for the doser such as pen-type injector, this doser is realized and being bestowed from the medical product of multiple dose cartridge case by injection, and the variable dose that the given dose scope that wherein, user can be allowed by equipment mechanism is selected medicine with step or the unit of increase.Dosing mechanism comprises dose (for example, digital sleeve) and drive member (for example, drive sleeve).Can provide other parts, for example housing, clutch and click generator (clicker).In addition, the present invention relates to a kind of injection device with this dosing mechanism.

In more detail, the present invention relates to a kind of dosing mechanism for reducible doser, it uses two-part drive sleeve, and this two-part drive sleeve is being alloted and between allotment period, should kept connecting, and only at user, presses piston rod so that device is separated while resetting.Reducible doser allows user to change or replace and hold the cartridge case of medicine, and makes dosing mechanism be reset to original state, thereby allows to use new cartridge to carry out dosage setting and dose distribution.

Background technology

In having the reusable pen of two-piece type drive sleeve, the two half-unit of drive sleeve is being alloted and is being connected between allotment period, but when new cartridge is installed separation so that piston rod can reset.The incipient fault pattern of this design is, if attached syringe needle stops up, if or user is forgotten attached syringe needle, and user is attempted to carry out administered by pressing dose button, dose button is advanced starting, numeral sleeve will start rotation (counting from " setting " dosage) downwards, and piston rod will start to advance along far-end (along cartridge case direction), thereby make the Crumple element of cartridge case, for example seal rubbery stopper and/or the diaphragm of rubber of the needle end of cartridge case, compression or distortion, until cartridge case stopper becomes and is enough to resist the power of the user applying the pressure of piston rod, then distributor gear will block.This generally occurs within the movement of several mm of piston rod (that is within several " units " that, digital sleeve shows).The resistance increment of mobile dose button and distributor gear block warning user: even if than the little numeral of " setting " dosage (digital sleeve shows now, numeral sleeve seems to show the dosage of " part is distributed "), this mechanism is not correct work (that is, medicine is not assigned with) also.If then user discharges the pressure to dose button, the Crumple element of cartridge case will tend to return its initial condition, thereby cause the pressure on piston rod, this pressure will make piston rod mobile along near-end (along the direction of dosing mechanism), this causes again device to enter reset mode, this is by the pressure in mitigation system, and distributor gear can be operated again by making dose button again start the power of mobile required user, thereby return to values for normal operation, that is, the operating value before blocking generation.At reseting period, the digital sleeve that not resetted by piston rod affects will continue to show the dosage of " part is distributed ".If syringe needle still stops up, and attempted that this is not sent or be obviously part send dosage time, user repeats this and presses the circulation with releasing dosage button, this device repeatedly blocks and oneself's reset simultaneously, numeral sleeve seems to show that this device take some units minute medicine that is the stage, and digital sleeve finally returns and shows zero unit,, numeral sleeve seems to show " completing dosage ", but does not now in fact distribute any medicine.

Summary of the invention

Therefore, the object of this invention is to provide a kind of improved and compact dosing mechanism for reducible pen device of eliminating this incipient fault pattern.

This dosing mechanism limiting by claim 1 is realized.Dosing mechanism of the present invention can be used in the device that uses two-part drive sleeve, this two-part drive sleeve is alloted and dosage keeps between allotment period connecting at dosage, and only when user is pressed piston rod so that device while resetting, for example, while changing cartridge case, separation.Dosing mechanism according to the present invention comprises: dose, for example digital sleeve; Dose button; Drive member, drive sleeve for example, for during dose distribution along distal direction piston rod; First clutch; And spring assembly.

Usually, drive member comprises near-end drive member and the far-end drive member connecting releasedly via first clutch.Spring assembly is designed to near-end drive member and far-end drive member to be biased into coupled situation, makes between allotment period, not allow with dosage at dosage setting the relative rotation of these two parts of drive member.Preferably, first clutch connects near-end drive member and far-end drive member ，Bing mechanism reseting period separated near-end drive member and far-end drive member rotatably rotatably between allotment period with dosage at dosage setting.User for example during distribution increases the compression of spring assembly to the operation of dose button, therefore prevents that clutch is separated between the allotment period when power is applied to piston rod.

In addition, provide the engagement device being associated with near-end drive member and dose respectively.Described engagement device be designed and be arranged so that near-end drive member during dose distribution on distal direction with (entrain) dose, but all allow At All Other Times relative the moving axially on proximal direction with respect to dose of near-end drive member all.If mechanism is can resetting-mechanism, preferably, the dose button that engagement device (if can with other device together application) is only sent to mechanism when the distribution power for user is applied just allows relative the moving axially on proximal direction with respect to dose of near-end drive member while being pressed during dose distribution or after dose distribution, and at reseting period, when dose button is not depressed, stops relative moving axially.In the operation of normal non-distribution, near-end drive member is biased into the power being applied by spring assembly at engagement device place and contacts with dose.According to a preferred embodiment of the invention, engagement device can comprise the corresponding inside outstanding flange on the near-end that is arranged on the hook from the outstanding finger piece of the near-end of near-end drive member and is positioned at dose.

The above-mentioned design of dosing mechanism allow drive sleeve near-end half portion in the situation that dose button for example, because remaining stopper compression discharges together with far-end half portion of (, during user is attempted syringe needle with obstruction and divided the incipient fault pattern of medicine) and drive sleeve, along near-end, move.If two half-unit moves axially together, they are not separated, and device can not enter reset mode, thereby has eliminated incipient fault pattern.In this case, if new unplugged syringe needle has been installed, spring assembly (the near-end of the two half-unit by drive member moves and further compression) will make whole drive member again along far-end, be driven, thereby from syringe needle, divide medicine and alleviate the compression cartridge case, and recover to set the mutual relation between dosage in show dose on digital sleeve and mechanism.

Usually, engagement device comprises flange or the protuberance being arranged in near-end drive member and is arranged on corresponding flange or the protuberance in dose.Therefore, engagement device is formed on respectively in near-end drive member and dose.As an alternative, engagement device can comprise the independent parts that are attached to near-end drive member and/or dose.

According to a preferred embodiment of the invention, dosing mechanism also comprises for connecting releasedly drive member, the second clutch of near-end drive member and dose preferably.Described second clutch can comprise tube element, and this tube element has and at least one axial notch that is arranged on the splined engagement in near-end drive member.Therefore, second clutch is fixed to for example drive member of near-end rotatably, if second clutch is rotated via dose, drive member is rotated during dosage setting.The key interlocking of drive member and clutch closes can be by realizing more than a pair of corresponding spline and groove.

By allow near-end drive member with respect to dose moving to axial on proximal direction, prevented from attempting distributing device reset afterwards with obstruction syringe needle.Yet if the near-end of drive member and far-end half portion move along near-end at reseting period, this also can enter reset mode by holdout device when new cartridge is installed.This is because enter near-end half portion that reset mode need to prevent drive sleeve and carry out near-end move axially when the far-end of drive sleeve is separated by being driven along near-end.Therefore, according to a further aspect in the invention, provide for limiting near-end drive member and installed the device that move to axial of reseting period along proximal direction with respect to dose.Preferably, at least one axial notch with step is provided, step is positioned at the transition position from the first with less width of groove to the second portion with larger width of groove, and wherein, the width of spline is chosen to allow spline to slide in two parts of groove.Near-end half portion of drive member and second clutch are by bias voltage rotatably, make spline with comprise step, be the contacts side surfaces of the groove of spline, therefore, when near-end half portion of drive member is directed in groove, on near-end or distal direction, freely advance, but when the end of spline contacts with step, stop further near-end to move.Therefore, the step in axial notch can prevent that near-end drive member from moving at the near-end of reseting period.The resistance that the near-end of near-end half portion of drive member is moved also provides by near-end half portion of drive member and the frictional force between second clutch.Under the effect of normal reset force, the resistance that the near-end of the far-end of drive member is moved only needs enough to overcome the friction connecting in the far-end of drive member and the first clutch of near-end half portion.

Therefore, the supplementary features of this step have overcome the potential defect of device, this be because, when second clutch is connected to dose, at normal device reseting period, prevent the moving axially of near-end half portion of drive member, yet, after trial distributes with obstruction syringe needle, the second clutch that is fixed to dose button during distribution moves along far-end, and makes it separated with dose, so the end of spline has surpassed the step of groove.In the second situation, reality is helped for near-end half portion of drive member and the frictional force between second clutch rather than the near-end of near-end half portion of resistance, drive member moves.In addition, in this second situation, friction in first clutch between the near-end of drive sleeve and far-end half portion will than under normal reset case much higher times (because act on the power on piston rod, therefore via being threaded onto drive sleeve far-end, the trial being stoped by the feature of first clutch makes the power of drive sleeve far-end rotation, in the situation that have the cartridge case that stops up syringe needle, compares high a lot with normal reset force).Therefore under the condition that, near-end half portion of the frictional force sufficient to guarantee drive member in first clutch does not become separated at first clutch, carrying out near-end moves.

In normal operating, when user is pressed dose button, the step of the groove in second clutch must be by being positioned at the end of spline of the near-end of drive sleeve.Now, near-end half portion of drive member and the engagement device between dose move the far-end that prevents near-end half portion of drive sleeve.The friction in near-end half portion of drive sleeve of the resistance of the step in second clutch groove and second clutch is little with respect to the power of the obtainable user in dose button.Along with the end that step is crossed spline, user can be experienced the little brake force (this may be also favourable, because it contributes to provide certain palpable feedback of dose button, therefore helps prevent unexpected distribution) in dose button.

Spline in groove in second clutch and near-end drive member can exchange, to realize identical function.

Preferably, according to dosing mechanism of the present invention also comprise for by the spline of drive member with respect to the groove bias voltage of clutch and/or remain on the device of the position, angle of restriction.This has guaranteed step in clutch groove and the engaged at end of drive sleeve near-end spline, to prevent that drive sleeve from sliding along near-end at reseting period.

According to further developing of this design, for bias voltage and/or keep the device of spline to comprise click generator (clicker) mechanism.Preferably, click generator mechanism comprises two click generator parts, and each is provided with the corresponding ring gear on the relative end face that is positioned at these two click generator parts.Other corresponding ring gear can be arranged on the other end of one of them click generator part on the relative face with second clutch, for second clutch is biased into click generator releasedly.According to an embodiment, the first click generator part has two ring gears that are positioned on its end face, as for second clutch being aligned to the bias voltage feature of the first click generator part and the first click generator part being connected to releasedly to the click generator features of the second click generator part.The first click generator part is connected to housing parts rotatably by the outside axial splines on the first click generator and the inside axial notch in housing.In addition, the second click generator part has the axial notch engaging with axial splines on drive sleeve near-end, so that these two parts rotations connect.

With stop up syringe needle distribute after the potential defect of the above-mentioned design that whole mechanism can move along near-end with respect to dose and housing during releasing dosage button be that user can not be alloted subsequently up and down,, can not revise setting dosage that is.This be because, under this state, near-end drive member is shifted along near-end with respect to second clutch, therefore spring assembly is compressed, so the first click generator part and the second click generator part spin locking be (with distribution state time the same) together, this again by near-end drive member spin locking to housing.If in this case, user applies excessive moment of torsion to dose, because its rotation is connected to small size and the limited joint between them (this limited joint is because limited dose button stroke) of the spline in the near-end drive member of the first click generator part, these splines may break down because of plastic deformation, thereby cause plant failure or dosage mistake subsequently.

The scheme that solves this potential defect is to make the spline and the groove type that when dose button is pressed, engage with near-end drive member and the first click generator part become the spline/groove rounding.In this case, after distributing with obstruction syringe needle, if user attempts to make dose rotation, the spline rounding and groove will resist rotation, thereby allot moment of torsion, by being significantly greater than, overcome the required normal moment of torsion of click generator tooth, and this can provide clearly to user the feedback of " where have not to thereby do not continue to apply the larger moment of torsion of alloting ".If user still continues to attempt and allot, apply even larger moment of torsion, replace plastic deformation, the spline rounding will collide the groove rounding in the first click generator part below, and can not cause the permanent damage of device.

In syringe needle plugging fault situation, and in the situation that user applies the excessive moment of torsion of alloting to the mechanism of blocking, the spline and the groove that round are collided as described, second clutch, be therefore dose button will with digital engages, thereby except very high, allot moment of torsion, device can normally be alloted up and down.

As mentioned above, the correct way that overcomes this fault mode (that is, attempting distributing with obstruction syringe needle) is to stop up syringe needle with spendable needle head replacing, thereby allows medicine to overflow by syringe needle, and alleviates the compressive load on internal mechanism.If then user distributes by pressing dose button, they will receive the dosage of alloting.

According to a preferred embodiment of the invention, dose comprises and can rotate to set with respect to housing the dosage driver plate sleeve (or digital sleeve) of dosage.In addition, drive member can comprise drive sleeve, this drive sleeve can move with respect to housing member during dosage setting on the first axial direction, and can on the second axial direction, move with respect to housing member during dose distribution, the second axial direction is contrary with described the first axial direction.Preferably, the movement of drive sleeve during dosage setting comprises translational component and rotational component, for example, and along moving of spiral path.During dose distribution, preferably, drive sleeve only moves axially, that is, and and without any the component that rotatablely moves.

If second clutch is connecting dose and drive member and separate dose setting element and drive member rotatably during dose distribution rotatably during dosage setting, drive member is followed dose along the moving of spiral path during dosage setting, and acceptable dose setting element rotates with respect to drive member during dose distribution.Advantageously, dosing mechanism needs less power during dose distribution.

Accompanying drawing explanation

Below, with reference to schematic figures, as example, the present invention is described, in accompanying drawing:

Fig. 1 illustrates the partial cross section of dosing mechanism, and wherein dosage is alloted and dose button is pressed into (that is, in dose distribution pattern),

The dosing mechanism that Fig. 2 illustrates Fig. 1 in the situation that syringe needle stops up after a trial dosage partial cross section (dosage is still alloted) after releasing dosage button,

Fig. 3 illustrates the amplification details (be still dosage is alloted and dose button is pressed into) of the dosing mechanism of Fig. 1,

Another of dosing mechanism that Fig. 4 illustrates Fig. 1 amplifies details, and wherein dosage is alloted and dose button is released (that is, in dosage, alloting in pattern),

Fig. 5 illustrates another amplification details of the dosing mechanism of Fig. 4,

Fig. 6 Fig. 1,2 or 3 dosing mechanism be shown another amplify details,

Fig. 7 illustrates the sectional view of amplification details of the near-end drive member of Fig. 1,2 or 3 dosing mechanism,

Fig. 8 illustrates the perspective view of amplification details of the near-end drive member of Fig. 1,2 or 3 dosing mechanism,

Fig. 9 illustrates the perspective view of far-end drive member of the dosing mechanism of Fig. 1,

Figure 10 illustrates the perspective view of coupling of the dosing mechanism of Fig. 1,

Figure 11 illustrates the perspective view of near-end drive member of the dosing mechanism of Fig. 1,

Figure 12 illustrates the perspective view of the second click generator part of the dosing mechanism of Fig. 1,

Figure 13 illustrates the perspective view of the first click generator part of the dosing mechanism of Fig. 1,

Figure 14 illustrates the perspective view of second clutch element of the dosing mechanism of Fig. 1,

Figure 15 illustrates the exploded view of the parts of injection device.

The specific embodiment

Fig. 1 illustrates the dosing mechanism 1 of the typical injection device with click generator mechanism.This dosing mechanism comprises (inside) housing member 2, comprises the dose 3 of dosage driver plate sleeve or digital sleeve, the second clutch element 5 of the drive member 4 of drive sleeve form, tubulose and click generator 6.Second clutch element 5, between dose 3 and drive member 4, and is connected to drive member 4 by least one groove and corresponding spline rotatably.In addition, second clutch element 5 can move axially with respect to dose 3, for dose 3 is connected with separated rotatably with drive member 4.As shown in Fig. 1 and 14, second clutch element 5 utilizes face tooth 5a, the 5b of two groups of couplings, on the corresponding end-faces of the second clutch element 5 of the face tooth 5a of these two groups couplings, the inner face that 5b is arranged on dose 3 and tubulose.

In the accompanying drawings, show dosing mechanism, wherein, click generator 6 is divided into two parts: the first click generator part 6' and the second click generator part 6'', the first click generator part 6' and the second click generator part 6'' illustrate in greater detail in Figure 12 and 13.The first click generator part 6' splined, to housing member 2, therefore must rotate freely with respect to drive member 4 and second clutch element 5 during alloting.

With respect to second clutch element 5, in mode similar to the above, click generator tooth 6a, 6b are set, yet tooth 6a, 6b compare with tooth 5a, 5b has much shallow angle.These click generator teeth are provided for alloting the braking of dosage together with helical spring 7 and for the click of tangibly and audible feedback.In other words, allow to be separately positioned on click generator tooth 6a, 6b on the first and second click generator elements during dosage setting one be compressed on another.The first click generator part 6' only moves axially very little amount (equaling the height of the tooth 6d between the first click generator 6' and second clutch 5) during alloting, therefore it can be at spin locking after only very little displacement to axial to drive member 4, and well in the axial engagement in clutch teeth 5a, 5b.

The second click generator part 6'' parts always rotate and are connected to drive member 4 and axially move around, thereby along with click generator tooth 6a, 6b suppress and alternately compression and decompression click generator spring 7 each other during alloting.

Also for necessary axial force is provided, (spline joint is to drive member 4, and the clutch teeth 5a on as explained below) engages when dosage delivered finishes and during alloting subsequently next dosage with the clutch teeth 5b on digital sleeve 3 so that second clutch element 5 for spring 7.In this way, this spring 7 plays two functions.

Drive member comprises two building blocks: far-end drive member 4' and near-end drive member 4''.As shown in Figure 9, far-end drive member 4' can be provided with the female thread engaging with threaded piston rod 8.Near-end drive member 4'' shown in Figure 11 be by second clutch element 5 and click generator mechanism 6 around tube element (drive sleeve).Coupling 4''' as shown in figure 10 can be arranged to be attached to far-end half 4' of of drive member, thereby first clutch is provided, to allot and dosage connects two drive sleeve, half 4' of, 4'' rotatably between allotment period.Coupling and far-end half 4' of, only for manufacturing former thereby being provided as independent parts, once and be fixed together at device assembly process, they are just as a single part.Coupling 4''' is provided with tooth, and these teeth are under the coupled situation of drive member 4, at dosage setting and dosage between allotment period, and with the corresponding indented joint on near-end half 4'' of of drive member, this limits first clutch.During alloting, click generator spring 7 is biased into by the two half-unit of drive member the state that they connect.Yet, this two half-unit of drive member 4 can be separated, so that device resets, thereby allow the far-end drive member 4' that is screwed to piston rod 8 along near-end, to move under the effect of piston rod, and near-end drive member 4'' is via the spline joint of itself and click generator mechanism and second clutch and remain fixed in housing 2.

Fig. 1 illustrates the device that button 9 is depressed during dose distribution.This makes second clutch element 5 separated with clutch teeth 5a, 5b between digital sleeve 3, and compresses click generator spring 7.No matter whether click generator spring 7 is compressed to and presses and state, and the load of compressing this spring is all enough to prevent that click generator face tooth 6a, 6b are during distribution applied at user under any distribute loads of button departs from.Therefore, these click generator face teeth 6a, 6b lock these two click generator element 6', 6'' rotatably.Because distribution power is directly delivered to far-end drive sleeve 4' from spring 7, and far-end drive sleeve 4' pulls far-end drive sleeve 4'' effectively along distal direction, therefore during distribution first clutch without any making far-end and near-end drive sleeve half 4' of, the separated tendency of 4''.In addition, because the first click generator 6' splined is to housing member 2, the second click generator 6'' splined to far-end drive sleeve 4', so this effectively by whole drive sleeve 4 spin lockings to housing member 2.

Near-end drive member 4'' has flange 4a or the axle collar at its near-end, and this flange 4a or the axle collar engage with corresponding flange or the protuberance 3a of digital sleeve 3, thus in the far-end moving process at drive member 4'' during dose distribution with it.As illustrated in greater detail in Fig. 7 and 8, engagement device can comprise the corresponding inwardly outstanding flange 3a of the near-end that is arranged on the hook 4a from the outstanding finger piece of the near-end of near-end drive member 4'' and is positioned at dose 3.

If Fig. 2 illustrates dose button, be released, still exist the compression (for example, because attempting to distribute with the syringe needle stopping up) because of cartridge case stopper to act on the near-end axial force in far-end drive member, now what can occur simultaneously.Different from distal direction, the place at the flange 4a of near-end drive member 4'' with digital sleeve 3, near-end drive member 4'' moves freely on proximal direction with respect to digital sleeve 3.In other words, for example, while being released under dose button (cartridge case stopper and barrier film) in cartridge case exists the condition of residual compression, allow near-end drive member 4'' along near-end, to move together with far-end drive member 4'.If this two half-unit moves axially together, they are not separated, and this device does not enter reset mode.In the case, if new syringe needle has been installed, spring 7 will drive drive sleeve along distal direction, thereby minute medicine is until the compression stress in cartridge case is completely lax.

The supplementary features that allow device 1 to reset when new cartridge is installed are preferably provided, that is, preferably provide with the syringe needle stopping up and divide timing not prevent moving axially of near-end drive member 4'' but stop or limit the supplementary features that this moves axially (and pressing dose button also allow second clutch 5 to move with respect to the far-end of far-end drive sleeve 4'' during starting normal allocation) at normal device reseting period.In the first situation, second clutch 5 is separated with digital sleeve 3, and in the second situation, second clutch 5 connects, thereby causes second clutch 5 with respect to the different position to axial of near-end drive member 4''.Therefore, can add the feature between these two parts, to allow to move to axial in the first situation, but in the second situation, stop or limit this and move.

This feature shown in Fig. 3-5, wherein second clutch element 5 is by being formed on that the spline 4b of the longitudinal sensing on near-end drive member 4'' and the corresponding recesses 5c of second clutch 5 engage and key is locked into near-end drive member 4'', to prevent the relative rotation between clutch member 5 and drive member 4, relative the vertically moving that allows them between the two simultaneously.In groove 5c, step 5d is set, thereby only at normal reseting period, prevents that the near-end of near-end drive member 4'' from moving.In other words, groove 5c has the distal portions of larger width and the proximal part of less width, the transition position of step 5d between these two parts.Like this, depend on axial arranged in groove 5c of spline 4b, the near-end of spline 4b moves and by step 5d, is stoped or be allowed to guide spline 4b in the part with less width of groove 5c.As an alternative, one or more spline 4b can be arranged on the tube element of second clutch, and one or more groove 5c can be arranged in near-end drive member.

In order to ensure the step 5d in second clutch groove 5c and the spline 4b of drive sleeve near-end 4'', engage to prevent that drive sleeve from sliding along near-end at reseting period, the spline 4b in drive sleeve must be biased in the step 5d in second clutch.The indented joint of this splined engagement by the second click generator 6'' and near-end drive member 4'', the first and second click generator part 6', 6'' and second clutch 5 (tooth 5e) and the first click generator 6'(tooth 6d) angled of indented joint realize.In other words, angled tooth (5e between the first click generator 6', 6d) by the relative rotation of tending to introduce in the fitting limit of other indented joint or splined engagement between second clutch 5 and near-end drive member 4'', while making spline 4b at device reseting period or whenever user releasing dosage button by towards step 5d bias voltage.

In order to increase the robustness of click generator mechanism opposing user misuse, preferably form respectively the spline 4c of near-end drive member 4'' and/or the corresponding recesses 6c of the first click generator part 6', one of make in spline 4c and groove 6c at least to there is form or the profile rounding.Therefore, when attempting to distribute and when these parts are in position shown in Fig. 2 after releasing dosage button with the syringe needle stopping up, if user attempts to rotate dose 3, allot moment of torsion by significantly higher than overcoming click generator tooth 6a, the required normal moment of torsion of 6b, therefore user can obviously feel to have where not right, for example, syringe needle stops up and mechanism is blocked.Yet, if user continues to attempt and to allot, allow the groove collision below in the first click generator part of the spline that rounds, and plastic deformation do not occur, so can not cause the permanent damage of device.

As mentioned above, overcoming this correct way of " misusing " fault mode is to change the syringe needle stopping up, by making medicine discharge to alleviate cartridge case pressure by syringe needle.Then user can starting drive and is sent required dosage.

In a word, to move be to be designed to overcome user in the situation that syringe needle (or obstruction syringe needle has been installed) is not installed, to device, to apply the security feature of the fault mode of distribution power to the near-end of drive sleeve 4 (comprising proximal part 4'', possible coupling and distal portions 4').This produces very high power (for example,, if user applies the 2:1 gear ratio of 80N，Ze mechanism by the about 160N of rubber retainer transmission to cartridge case) in device.These high power are enough to cause rubber components (retainer and the barrier film) strain (as huge spring) of cartridge case.This distortion produces and makes the advance space of several units (an about 5-10 unit) of axle, and this can make again digital sleeve 3 cycles (make digital sleeve under the condition of not distributing any insulin demonstration now than the few 5-10 of " setting " dosage unit).

When user releasing dosage is dialled the power on handle (not shown), the elastic force in cartridge case presses support member backward, and this can make axle reset.Yet digital sleeve 3 remains on the numeral (lower than setting the about 5-10 of a dosage unit) of present minimizing.When mobile after taking care axially, device is resetted, and the pressure in cartridge case is released.Therefore, whole process can repeat.By each time " dosing dosage ", the numeral that digital sleeve 3 shows in dosage window will reduce by 5-10 unit.Finally, digital sleeve 3 will turn back to 0, and not distribute any insulin.

The scheme addressing this problem is, when very high load applying arrives axle, to allow whole drive sleeve 4 to move (that is, towards dosage, dialling handle moves) along near-end.Yet under normal reset load, this is less desirable, because if whole drive sleeve 4 moves along near-end together, far-end does not have relative moving axially with near-end drive sleeve 4', 4'', therefore can not depart to allow to reset.Under normal reset load (general 2-4N), must prevent that near-end drive sleeve part 4'' from moving along near-end.In order to ensure like this, the groove 5c on the clutch 5 engaging with rib (spline 4b) on the proximal part 4'' of drive sleeve 4 all has small stair 5d, so that the counteracting force of the movement of resisting near-end drive sleeve 4'' to be provided.Shallow bias voltage tooth on the end of the biasing force of spring 7 and the first click generator part 6' guarantees that the spline 4b of near-end drive sleeve 4'' always rotates (bias voltage) against the side that comprises the clutch groove 5c of this step 5d.

Under normal reset load (2-4N), unique power of tending to near-end drive sleeve 4'' is moved along proximal direction is far-end drive sleeve 4'(or its coupling) and near-end drive sleeve 4'' between friction.In this case, the near-end of near-end drive sleeve 4'' moves the friction of also dialling between handle by near-end drive sleeve 4'' and clutch 5, the first and second click generator part 6', 6'' and dosage and stops.Therefore, small stair 5d is favourable.

When user is attempted administered under the condition that syringe needle is not installed, dosage is dialled handle and is pressed into, so the step 5d of clutch 5 so clutch spline one side, with respect to the end of near-end drive sleeve spline, along far-end, moves.Therefore, when user releasing dosage is dialled handle, drive sleeve 4', 4'' and clutch 5 add that dosage dials handle and can all along near-end, move together, and at stopper to piston rod, be therefore to be also like this under the compression stress of far-end drive sleeve 4'.Therefore, in this case, the step 5d in clutch is incoherent, because do not exist and relatively move between near-end drive sleeve and clutch.

Dosing mechanism can be a part for injection device, and injection device also comprises the cartridge case that holds medicine.Cartridge case can be maintained in cartridge case keeper, and this cartridge case keeper can be permanently or is attached to releasedly dosing mechanism.

Term " medicine ", as used herein, refers to the pharmaceutical formulation that comprises at least one pharmaceutically active compound,

Wherein in one embodiment, pharmaceutically active compound has up to the molecular weight of 1500Da and/or is peptide, protein, polysaccharide, vaccine, DNA, RNA, enzyme, antibody or its fragment, hormone or oligonucleotide, or the mixture of above-mentioned pharmaceutically active compound,

Wherein in another embodiment, pharmaceutically active compound be used for the treatment of and/or prevent diabetes or the complication relevant to diabetes as diabetic renal papillary necrosis, thromboembolism disease is as dark vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina pectoris (angina), myocardial infarction, cancer, degeneration of macula, inflammation, pollinosis, atherosclerosis and/or rheumatoid arthritis

Wherein in another embodiment, pharmaceutically active compound comprise at least one be used for the treatment of and/or prevent diabetes or the complication relevant to diabetes as the peptide of diabetic renal papillary necrosis,

Wherein in another embodiment, pharmaceutically active compound comprises at least one insulin human or human insulin analogue or derivant, glucagon-like peptide (GLP-1) or its analog or derivant, or exendin-3 or exendin-4, or the analog of exendin-3 or exendin-4 or derivant.

Insulin analog is for example Gly (A21), Arg (B31), Arg (B32) insulin human; Lys (B3), Glu (B29) insulin human; Lys (B28), Pro (B29) insulin human; Asp (B28) insulin human; Insulin human, wherein the proline of B28 position is substituted by Asp, Lys, Leu, Val or Ala, and wherein the Lys of B29 position can be substituted by Pro; Ala (B26) insulin human; Des (B28-B30) insulin human; Des (B27) insulin human and Des (B30) insulin human.

Insulin derivates is for example B29-N-myristoyl-des (B30) insulin human; B29-N-palmityl-des (B30) insulin human; B29-N-myristoyl insulin human; B29-N-palmityl insulin human; B28-N-myristoyl Lispro; B28-N-palmityl-Lispro; B30-N-myristoyl-ThrB29LysB30 insulin human; B30-N-palmityl-ThrB29LysB30 insulin human; B29-N-(N-palmityl-Υ-glutamy)-des (B30) insulin human; B29-N-(N-stone gallbladder acyl-gamma-glutamyl)-des (B30) insulin human; B29-N-(ω-carboxyl heptadecanoyl)-des (B30) insulin human and B29-N-(ω-carboxyl heptadecanoyl) insulin human.

Exendin-4 for example refers to Exendin-4 (1-39), and a kind of sequence is H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Me t-Glu-Glu-Glu-Al a-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Se r-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH ₂peptide.

Exendin-4 derivant is for example selected from following compounds:

H-(Lys)4-des?Pro36,des?Pro37Exendin-4(1-39)-NH2，

H-(Lys)5-des?Pro36,des?Pro37Exendin-4(1-39)-NH2，

des?Pro36Exendin-4(1-39)，

des?Pro36[Asp28]Exendin-4(1-39)，

des?Pro36[IsoAsp28]Exendin-4(1-39)，

des?Pro36[Met(O)14,Asp28]Exendin-4(1-39)，

des?Pro36[Met(O)14,IsoAsp28]Exendin-4(1-39)，

des?Pro36[Trp(O2)25,Asp28]Exendin-4(1-39)，

des?Pro36[Trp(O2)25,IsoAsp28]Exendin-4(1-39)，

des?Pro36[Met(O)14Trp(O2)25,Asp28]Exendin-4(1-39)，

Des Pro36[Met (O) 14Trp (O2) 25, IsoAsp28] Exendin-4 (1-39); Or

des?Pro36[Asp28]Exendin-4(1-39)，

des?Pro36[IsoAsp28]Exendin-4(1-39)，

des?Pro36[Met(O)14,Asp28]Exendin-4(1-39)，

des?Pro36[Met(O)14,IsoAsp28]Exendin-4(1-39)，

des?Pro36[Trp(O2)25,Asp28]Exendin-4(1-39)，

des?Pro36[Trp(O2)25,IsoAsp28]Exendin-4(1-39)，

des?Pro36[Met(O)14Trp(O2)25,Asp28]Exendin-4(1-39)，

des?Pro36[Met(O)14Trp(O2)25,IsoAsp28]Exendin-4(1-39)，

Wherein said group-Lys6-NH2 can be bonded to the C-end of Exendin-4 derivant;

Or there is the Exendin-4 derivant of following sequence

des?Pro36Exendin-4(1-39)-Lys6-NH2(AVE0010)，

H-(Lys)6-des?Pro36[Asp28]Exendin-4(1-39)-Lys6-NH2，

des?Asp28Pro36,Pro37,Pro38Exendin-4(1-39)-NH2，

H-(Lys)6-des?Pro36,Pro38[Asp28]Exendin-4(1-39)-NH2，

H-Asn-(Glu)5des?Pro36,Pro37,Pro38[Asp28]Exendin-4(1-39)-NH2，

des?Pro36,Pro37,Pro38[Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-(Lys)6-des?Pro36,Pro37,Pro38[Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-Asn-(Glu)5-des?Pro36,Pro37,Pro38[Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-(Lys)6-des?Pro36[Trp(O2)25,Asp28]Exendin-4(1-39)-Lys6-NH2，

H-des?Asp28Pro36,Pro37,Pro38[Trp(O2)25]Exendin-4(1-39)-NH2，

H-(Lys)6-des?Pro36,Pro37,Pro38[Trp(O2)25,Asp28]Exendin-4(1-39)-NH2，

H-Asn-(Glu)5-des?Pro36,Pro37,Pro38[Trp(O2)25,Asp28]Exendin-4(1-39)-NH2，

des?Pro36,Pro37,Pro38[Trp(O2)25,Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-(Lys)6-des?Pro36,Pro37,Pro38[Trp(O2)25,Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-Asn-(Glu)5-des?Pro36,Pro37,Pro38[Trp(O2)25,Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-(Lys)6-des?Pro36[Met(O)14,Asp28]Exendin-4(1-39)-Lys6-NH2，

des?Met(O)14Asp28Pro36,Pro37,Pro38Exendin-4(1-39)-NH2，

H-(Lys)6-desPro36,Pro37,Pro38[Met(O)14,Asp28]Exendin-4(1-39)-NH2，

H-Asn-(Glu)5-des?Pro36,Pro37,Pro38[Met(O)14,Asp28]Exendin-4(1-39)-NH2，

des?Pro36,Pro37,Pro38[Met(O)14,Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-(Lys)6-des?Pro36,Pro37,Pro38[Met(O)14,Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-Asn-(Glu)5des?Pro36,Pro37,Pro38[Met(O)14,Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-Lys6-des?Pro36[Met(O)14,Trp(O2)25,Asp28]Exendin-4(1-39)-Lys6-NH2，

H-des?Asp28Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25]Exendin-4(1-39)-NH2，

H-(Lys)6-des?Pro36,Pro37,Pro38[Met(O)14,Asp28]Exendin-4(1-39)-NH2，

H-Asn-(Glu)5-des?Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]Exendin-4(1-39)-NH2，

des?Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]Exendin-4(1-39)-(Lys)6-NH2，

H-(Lys)6-des?Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]Exendin-4(S1-39)-(Lys)6-NH2，

H-Asn-(Glu)5-des?Pro36,Pro37,Pro38[Met(O)14,Trp(O2)25,Asp28]Exendin-4(1-39)-(Lys)6-NH2；

Or any pharmaceutically acceptable salt or solvate in aforementioned Exendin-4 derivant.

Hormone is for example hypophysis hormones or hypothalamic hormone class or modulability bioactive peptide and their antagonist, as Rote Liste, 2008 editions, listed in the 50th chapter, as promoting sexual gland hormone (Gonadotropine) (follicle stimulating hormone (Follitropin), lutropin (Lutropin), chorionic-gonadotropin hormone (Choriongonadotropin), thylakentrin (Menotropin)), growth hormone (Somatropine) (growth hormone (Somatropin)), Desmopressin (Desmopressin), terlipressin (Terlipressin), gonadorelin (Gonadorelin), triptorelin (Triptorelin), leuprorelin (Leuprorelin), buserelin (Buserelin), nafarelin (Nafarelin), goserelin (Goserelin).

Polysaccharide is for example glucosaminoglycan, hyaluronic acid, heparin, low molecular weight heparin or ultra-low molecular weight heparin or their derivant, or the sulphation form of above-mentioned polysaccharide, for example, and poly sulphation form, and/or their pharmaceutically acceptable salts.The example of the pharmaceutically acceptable salt of poly sulphation low molecular weight heparin is Enoxaparin Sodium (enoxaparin sodium).

Antibody is spherical plasma proteins (～150kDa), and it is also called the immunoglobulin of enjoying basic structure.Because they have the sugar chain that is added into amino acid residue, so they are glycoproteins.The basic functional units of each antibody is immunoglobulin (Ig) monomer (only containing an Ig unit); Secretion antibody also can be there are two Ig unit dimer as IgA, there is the tetramer of four Ig unit as bony fish (teleost fish) IgM, or there is the pentamer of five Ig unit, as mammal IgM.

Ig monomer is the molecule of " Y "-shape, and it is comprised of four polypeptide chains; Two identical heavy chains and two identical light chains, they are connected by the disulfide bond between cysteine residues.Each heavy chain is about 440 aminoacid; Each light chain is about 220 aminoacid.Heavy chain and light chain respectively contain the disulfide bond in chain, and it stablizes the folding of them.Each chain comprises the domain that is called Ig territory.These territories contain 70-110 the aminoacid of having an appointment, and can be different classifications (for example, variable or V, constant or C) according to their size and functional classification.They have distinctive immunoglobulin folding, and wherein two β lamellas (β sheet) have created " sandwich " shape, and it is kept together by the interaction between the cysteine of guarding and other charged aminoacid.

The mammal Ig heavy chain that has five kinds, is expressed as α, δ, ε, γ and μ.The type definition of the heavy chain existing the isotype of antibody; These chains see respectively IgA, IgD, IgE, IgG and IgM antibody.

The heavy chain of uniqueness is in size and form different: α and γ contain containing have an appointment 450 aminoacid and δ 500 aminoacid of having an appointment, and μ and ε have approximately 550 aminoacid.Each heavy chain has two regions, constant region (CH) and variable region (VH).In species, constant region is substantially the same in all antibody of same isotype, but it is different in the antibody of different isotypes.Heavy chain γ, α and δ have constant region, and it comprises or consists of the Ig territory of three series connection, and for adding flexible hinge region; Heavy chain μ and ε have constant region, and it comprises or consists of four immunoglobulin territories.The variable region of heavy chain is different in the antibody being produced by different B cell, but it is same for all antibody that produced by single B cell or B cell clone.The variable region of each heavy chain is about 110 aminoacid and comprises or consist of single Ig territory.

In mammal, there is the light chain immunoglobulin of two kinds, be expressed as λ and κ.Light chain has two territories in succession: a constant domain (CL) and a variable domain (VL).The approximate size of light chain is 211 to 217 aminoacid.Each antibody contains two light chains, and it is always identical; Only there is the light chain of a kind in each antibody in mammal, κ or λ.

Although the general structure of all antibody is closely similar, the peculiar property of given antibody is definite by variable (V) district, as detailed above.More specifically, variable loop, its on each light chain on (VL) and heavy chain (VH) respectively have three, be responsible for the combination to antigen, be responsible for antigenic specificity.These rings are called complementary determining region (Complementarity Determining Regions, CDRs).Because the CDRs from VH and VL territory has contribution to antigen binding site, thus be the combination of heavy chain and light chain, but not any one is independent, has determined final antigenic specificity.

" antibody fragment " contains at least one Fab as defined above, and substantially presents same function and the specificity of complete antibody of originating with antibody fragment.With the limited proteolysis digestion of papain, Ig prototype is cut into three fragments.Two identical amino terminal fragments, each contains a complete L chain and only about half of H chain, is Fab (Fab).The 3rd fragment, half of the similar but carboxyl terminal that contains two heavy chains with interchain disulfide bond of its size, is FC (Fc).Fc contains carbohydrate, complement-combination and FcR-binding site.Restricted pepsin digestion produces single F (ab') 2 fragments, and it contains two Fab sheets and hinge region, comprises H-H interchain disulfide bond.For antigen, combination is bivalence to F (ab') 2.Can be by the disulfide bond cracking of F (ab') 2 to obtain Fab'.In addition, the variable region of heavy chain and light chain can be merged to together with to form single chain variable fragment (scFv).

Pharmaceutically acceptable salt is for example acid-addition salts and basic salt.Acid-addition salts is the salt of HCl or HBr for example.Basic salt is for example to have the cationic salt that is selected from alkali or alkaline matter (alkali or alkaline), described cation is Na+ for example, or K+, or Ca2+, or ammonium ion N+ (R1) (R2) (R3) (R4), wherein R1 to R4 refers to independently of one another: hydrogen, the C1-C6-alkyl optionally replacing, the C2-C6-thiazolinyl optionally replacing, the C6-C10-aryl optionally replacing, or the C6-C10-heteroaryl optionally replacing.Other example of pharmaceutically acceptable salt has been described in the 17th edition < < Remington's Pharmaceutical Sciences > > edit by Alfonso R. Gennaro publishing at the Mark Publishing Company of Pennsylvania, America Easton in 1985 and encyclopaedical (Encyclopedia of Pharmaceutical Technology) the > > of < < preparation technique.

Pharmaceutically acceptable solvate is hydrate for example.

Reference numeral:

1 dosing mechanism

2 housing members

3 digital sleeves (dose)

3a protuberance

4 drive sleeve (drive member)

4' far-end drive member

4'' near-end drive member

4''' coupling

4a flange

4b spline

4c spline

5 (the second) clutch members

5a, 5b clutch teeth

5c groove

5d step

The angled tooth of 5e

6 click generators

6a, 6b click generator tooth

6c groove

The angled tooth of 6d

6' the first click generator part

6'' the second click generator part

7 click generator springs

8 piston rods

9 buttons

Claims

1. for doser, preferably the dosing mechanism ，Gai mechanism of reducible doser comprises:

Dose (3),

Drive member (4), for during dose distribution along distal direction piston rod, (4') this drive member (4) comprises near-end drive member (4'') and far-end drive member,

First clutch, for (4') near-end drive member (4'') and far-end drive member are connected releasedly,

Spring assembly (7), between allotment period, (4') near-end drive member (4'') and far-end drive member being biased into coupled situation at dosage setting and dosage, and

Engagement device (3a, 4a), is associated with near-end drive member (4'') and dose (3),

Wherein, engagement device (3a, 4a) be designed and be arranged so that near-end drive member (4'') during dose distribution on distal direction with dose (3), but allow near-end drive member (4'') relative moving axially on proximal direction with respect to dose (3).

2. according to the dosing mechanism of claim 1, it is characterized in that, this mechanism is the reducible mechanism that also comprises dose button, dose button is sent to described mechanism for the distribution power that user is applied, wherein, engagement device (3a, 4a) only when dose button is pressed during dose distribution or after dose distribution, just allow near-end drive member (4'') relative moving axially on proximal direction with respect to dose (3), and at reseting period, when dose button is not depressed, resist relative moving axially.

3. according to the dosing mechanism of claim 1 or 2, it is characterized in that, engagement device (3a, 4a) comprises the flange (4a) being arranged in near-end drive member (4'') and is arranged on the corresponding protuberance (3a) in dose (3).

4. according to the dosing mechanism of any one in aforementioned claim, it is characterized in that, first clutch at dosage setting, connect rotatably between allotment period with dosage near-end drive member (4'') and far-end drive member (4') ，Bing mechanism reseting period separated near-end drive member (4'') and far-end drive member be (4') rotatably.

5. according to the dosing mechanism of any one in aforementioned claim, it is characterized in that, when near-end drive member (4'') does not move on proximal direction with respect to dose (3), first clutch will be separated rotatably, thereby allow the reset of piston rod.

6. according to the dosing mechanism of any one in aforementioned claim, also comprise for connecting releasedly the second clutch (5) of near-end drive member (4'') and dose (3), it is characterized in that, second clutch (5) comprises tube element, and this tube element has at least one axial notch (5c) engaging with the spline (4b) being arranged in near-end drive member (4'').

7. according to the dosing mechanism of claim 6, it is characterized in that, described at least one axial notch (5c) is provided with step (5d), this step (5d) is positioned at the transition position from the first with less width of groove (5c) to the second portion with larger width of groove, wherein, the width of spline (4b) is chosen to allow spline to slide in two parts of groove (5c).

8. according to the dosing mechanism of claim 7, it is characterized in that, the step (5d) in axial notch (5c) prevents that the near-end of reseting period near-end drive member (4'') from moving.

9. according to the dosing mechanism of claim 6 or 7, also comprise for by spline (4b) with respect to groove (5c) bias voltage and/or remain on the device of position, angle.

10. according to the dosing mechanism of claim 9, it is characterized in that, for bias voltage and/or keep the device of spline (4b) to comprise for connect releasedly the click generator mechanism (6) of second clutch (5) and near-end drive member (4'') at mechanism's reseting period.

11. according to the dosing mechanism of claim 10, it is characterized in that, click generator mechanism (6) comprises two click generator parts: the first click generator part that rotation is connected to clutch (5) is releasedly fixed to the second click generator part (6'') of near-end drive member (4'') (6'), rotatably, and, these two click generator parts (6', 6'') each other rotation releasedly connect.

12. according to the dosing mechanism of any one in claim 10 or 11, it is characterized in that, (6') the first click generator part engages with corresponding click generator groove (6c) by click generator spline (4c) and is fixed to rotatably near-end drive member (4''), wherein, click generator spline (4c) and/or click generator groove (6c) have the profile rounding.

13. according to the dosing mechanism of any one in aforementioned claim, it is characterized in that, second clutch (5) connects rotatably dose (3) and drive member (4) during dosage setting, and during dose distribution separate dose setting element (3) and drive member (4) rotatably.

14. injection devices, comprise according to the dosing mechanism of any one in aforementioned claim and are preferably contained in the medicine in cartridge case.